Hydroxy amides Synthesis

N. Kambe, T. Inoue, and N. Sonoda 154 SYNTHESIS OF AN a-HYDROXY-AMIDE N.N-DIETHYL-2-HYDROXY-4-PHENYLBUTANAMIDE. GENERATION OF N.N-DIETHYL-CARBAMOYLLITHIUM VIA LITHIUM-TELLURIUM EXCHANGE AND ITS REACTION WITH 3-PHENYLPROPANAL... 

The actual synthesis (Scheme 21) started with the stereoselective alkylation of Myers hydroxy-amide 131 [40] followed by reductive removal of the auxiliary to give 132 in high yield and enantioselectivity. Wittig olefination furnished enoate 133, which was then elaborated into the (E)-l-acetoxy-diene 129 using... 

Scheme 33 Synthesis of 3-hydroxy amides catalyzed by NHCs...

By analogy with the synthesis of a-hydroxy acids one can envisage a one-pot synthesis of a-hydroxy amides from aldehydes via hydrocyanation and in situ NHase-catalyzed hydrolysis to the amide. Since enantioselective NHases are very rare, the enantioselectivity should be derived from HnL-catalyzed hydrocyanation. The second step has been described for the Rhodococcus erythropolis NHase-catalyzed hydration of (R)-mandelonitrile to give the (R)-amide with retention of enantiopurity [43]. 

In their synthesis of (+)-calyculin A and (—)-calyculin B, Smith and co-workers observed partial epimerization when the (3-hydroxy amide 4 was reacted with SOCI2 despite the mild reaction conditions, 4 °C in tetrahydrofuran (THF)." The mechanism of this epimerization was not discussed (Scheme 8.5). 

Wuts and co-workers recently reported that the Vilsmeier reagent is superior to thionyl chloride for the cyclodehydration of primary and secondary p-hydroxy amides to prepare oxazolines, in particular, for oxazoline 18b, which is used in Taxol synthesis (Scheme 8.10). Some other examples are shown in Table 8.5 (Fig. 8.3). As expected, inversion of configuration at the alcohol bearing carbon atom is observed. Of the examples examined, serine afforded low yields due to the formation of dehydroalanine. The reaction is conveniently carried out in pyridine at room temperature. p-Chloro amides are also formed, which can be converted to the oxazoline with DBU, generally using the same mixture without isolation. The... 

Phosphorous oxychloride (POCI3) can also be used without further activation. For the synthesis of the antidepressant (/ )-(—)-rolipram 24, cyclization of the (3-hydroxy amide 21 with POCI3 gave the oxazoline intermediate 22. Diastereo-selective conjugate addition of cyanide gave the cyano derivative 23, which was further transformed to (/ )-( )-rolipram (Scheme 8.11). 

Partial hydrolysis of an oxazoline to produce the hydroxy amide was used extensively in the synthesis of Taxol analogues (Table 8.24 Scheme It is noteworthy that a solution of the amino... 

Further discussion and additional references to the synthesis of peptides containing dide-hydro-a-amino acids, reduced peptide isosteres, TV-hydroxy amides and hydrazides, and Ca-tetrasubstituted amino acids including 2,3-methano amino acids can be found in Sections 11.1,10.7,10.8, and 10.3, respectively. 

Appropriately substituted hydroxy amides and ureas can be used instead of diamines. Thus, acid-catalyzed cyclocondensation of iV-carbamoyl prolinols 137 (R1 = H, (CH2)3) (Scheme 27) with aldehydes RCHO (R = Ph, 2-MeOC6H4, 2-naphthyl, etc.) stereoselectively afforded a series of pyrroldine-fused oxadiazepinones 46 (Scheme 5) <1990CPB2627, 1990H(30)287, 1996LA927>. Similar heterocyclization of 4-(2-hydroxyethylthio)-2-azetidinone with acetone dimethyl acetal was used in the synthesis of azetidinone-fused oxathiazepanes of type 33 (X = S) (Figure 4) <1980JA2039>. 

This method was successfully applied to the total synthesis of ( )-dihydrocorryl-nantheol (130). As detailed in Scheme 25, substrate 128 was derived from 126. Condensation of 128 with tryptamine, mesylation of the resulting hydroxy amide, and then ring closure using KH and 18-crown-6 in DME (1,2-dimethoxyethane) led to lactam 129 in 70% overall yield. 

During model studies directed towards the synthesis of the Mycalamides, Hoffmann and co-workers 41 discovered a reduction reaction which accompanied the deprotection of an /V-SEM derivative [Scheme 8.152]. Treatment of 152 1 with TT1AF in DMPU at 45 returned the a-hydroxy amide 152 2 as a 3 1 mixture of diastereoisomers. The authors speculate that the reduction reaction was caused by a reagent of the type N-CH2-0 or F-CH2-0 derived from cleavage of the SEM group. The reduction was a welcome and useful surprise since the nascent hydroxyl group is present in the natural product. 

Keck and co-workers have shown that this Diels-Alder reaction offers promise for the synthesis of certain alkaloids and other nitrogen-containing products since the adducts are selectively cleaved to hydroxy amides by aluminum or sodium amalgam. 

Synthesis [31] of hydroxy amides 39 and 41, that were intermediates on the route to dopamine D3/D5 receptor antagonists, involved the Smiles re-... 

Oxazolidinediones are generally readily prepared from amino acids and hydroxy-amides with a carbonate equivalent such as carbonyldiimidazole or diethyl carbonate itself. Isothiocyanates can also be used as starting materials for the synthesis of 2,5-oxazolidinediones (Equation 25) <2006TL3953>. 

The compound [2- C]5,5-dimethyloxazolidine-2,4-dione (10.47), used for the estimation of intracellular pH, is prepared by reaction of COCl with a dry ethanolic solution containing 2-hydroxy-2-methylpropanamide and sodium ethoxide [180,181]. This procedure involves the synthesis of diethyl carbonate in situ, which reacts in turn with the hydroxy amide [759]. 

Akiyama, M., Iesaki, K., Katoh, A., and Shimizu, K. (1986) N-hydroxy amides.5. Synthesis and properties Of N-hydroxypep-tides having leucine enkephalin sequences. J. Chem. Soc. Perkin. 1, 851-855. 

Mai A et al (2005) Class II (Ila)-selective histone deacetylase inhibitors. 1. Synthesis and biological evaluation of novel (aryloxopropenyl)pyrrolyl hydroxy amides. J Med Chem 48(9) 3344-3353... 

Several natural products, for example siderophores, contain the N-hydroxy amide Y[CON(OH)] motif [138], Within a peptide backbone, this group increases the stability to enzyme degradation and induces characteristic conformational behavior [139]. In addition to the synthesis in solution of N-hydroxy amide-containing peptides (which is not trivial), a new solid-phase approach has recently been developed [140]. To explore the features of the N-hydroxy amide moiety using automated and combinatorial techniques, a method for the preparation of v /[CON(OH)] peptide ligands for MHC-I molecules has been elaborated [140], The strategy for the parallel preparation of these peptidomimetics on a solid support is illustrated in Scheme 7.9. The key step is the nucleophilic substitution reaction of resin-bound bromocarboxylic acids by O-benzylhydroxylamine, which requires several days. 

Scheme 7.9. Solid-phase synthesis of N-hydroxy amide ty[CON(OH)] peptide bond analogues [140].

A stereospecific synthesis of (+ )-/3-lycorane has been reported (75). Catalytic reduction of the Diels-Alder adduct (XXIV) proceeded with 0 N acyl migration to form a hydroxy amide which was oxidized to the... 

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